BG98254A - Crystalline oxathiolane derivatives - Google Patents

Abstract

The invention relates to (-) - cis -4-amino-1- (2-hydroxymethyl-1,3-oxathiolan-5- yl) - (1 H) -pyrimidin-2-one in crystalline form, or bipyramidal crystals, to pharmaceutical forms of the compounds and to methods for their preparation and use in medicine.

Description

This invention relates to nucleoside analogues for their use in medicine. In particular, the invention relates to 1,3-oxathiolanone nucleoside analogues, to these pharmaceutical prodrugs, as well as to their derivatives, and to the use or to the treatment of specific physiological viral infections.

(I) also known as ECH-189 or N6PB-21 has been described as having antiviral activity, particularly with regard to human immunodeficiency virus (HIV) viruses, which are the causes The compound with the compound (I) is A, NH,

X

/ 1-2 /

1 / and /.-2/:

/ RTI > and has been described and tested under the farm. For a racemate, the compound, generally approved for the treatment of conditions caused by HB, is 3'-azido-3 apos; -deoxythymidine (A2T, zidovudine, BW 5090). However, when using this compound, there is no possibility of a side effect, which can not be administered or once administered, it is necessary to stop its administration in a significant number of patients. Therefore, there is a continuing need for compounds that are eczemic against HNE, but. at the same time, they are inherently higher therapeutic index. Although the bintiomers of the compound of formula (I) are of equal magnitude against wild-type, the enantiomer has a significantly lower cytotoxicity than the other enantiomer and is therefore preferred as an antiviral agent. (-) - 1 - [(1 H-pyrimidin-2-oxime) -1- (2-hydroxyiminomethyl) . is the stereochemistry of the compound with the formula (±) - with the name of (2α, 5β) -trimethylamino-5-hydroxymethyl-1, -one. The compound is now fused as a FTT. g / d DGs in essence; preferably from the (+) enantiomer, i.e., the weight / weight of the (+) enantiomer, in dc; in particular, more than 1% w / w. In U.S. Pat. No. 3,403,133, the preparation of 3TC is described, the application of U.S. Pat. ç ð ð ð ð ò ò ò ò ò ò ò ò ò ò ò ò ò ò ò ò ò ò ò ò ò ò ò ò ò ò ò ò ò ò ò ¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿" n is the same as in Fig. UGGCd \\\ 'C5'i (

Jiric

-> 0 Bid. ¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿' Therefore, the first aspect of the invention relates to the crystalline. PTC. When crystallized from an aqueous solution, 3TC is obtained from needle-like crystals (from Example 1). This type of crystals are not suitable for the preparation of solid-pharmaceutical preparations due to the presence of solvents. J DODO rdi-iQiiiiCojy * j piOIIIS. Td-D-GCGT-V / GTcL < / RTI > is known to occur under certain conditions, for a long time, the SxC can be obtained under the presence of desopramide crystals (hereinafter referred to as the crystals) of the drug have improved fluidity, and this is preferred in the case of formulated medicaments.In addition, crystalline ones and, in some cases, crystalline racemates in the vessel, such as milling, and the occurrence of some undesirable - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - When the CTC is used for the preparation of a compound of the formula I or II, -170 ° C and in particular 177-178 ° C

Jr \

J JOURNAL. / RTI &gt; and / or < RTI ID = 0.0 > 0 &lt; / RTI &gt; T-ObrG3. I P / Thr-1 / -. iiP-C ^ P *! and the temperature is about 124-127 ° C when it is clear. - i & i. P Art. J_ heard C'lx /; COPPER CURRENT MICROCHEMICAL CIRCUIT BACKGROUND OF THE INVENTION, which is absent in splices, in particular shows that strong absorptive bands at approximately 920 and 850 wavelengths. Anode I at 1110 wavelength is missing- _______. u. *. 'V'y. those drPs in Cii C <iJ. ¿¿¡¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿ ¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿ , p. 177-178e, UQ.

ZL • · · * * * * * * - * * * * * - * * -. -w. - - --------.- scanning calorimetry with an initial temperature of 124-127 ° C. Thus, another aspect of the invention relates to the crystallisation of crystalline crystals. According to a third aspect of the invention, 3TC is the subnormal of bipyrachidate crystals. The object of the study is also 3C at a crystalline melting point above 170 ° C, in particular 177-178 ° C. Alternatively, a 3TC crystalline standard is provided which shows an endothermic probe in case of scanning capiimetry (SC) -178 ° C. another alternative provides a 3TC crystalline porosity which has MSOMs at around about 50 and around PdF wavelengths in its infrared spectrum. In particular, it is ensured that the crystalline FCPX of the 3TC, which, in addition to the aforesaid aortic spheres, is provided with a strip of absence at a distance of 0 to 10 cm. Thirty days before the end of the day. -. It has been separated from its enantiomers. In particular, the 3TC can be obtained from the known racemate by chiral fluid host hypothyroidism, by enzyme-specific selective catabolism with an oligosaccharide enzyme such as cytidine deaminase or selective enzymatic degradation of a suitable opioid, by using 3CTC 9 in the form of a compound of the formula I as defined in claim 1, by the crystallization of the compound from an aqueous solution, or by the addition of propan-1-ol, in the presence of propanol, t, t, t, t, t, t, t, t, t, t, t, t, t, n, -specifically from Hincin (Cg.alkoxon) such as ethanol, industrial denatured ethanol or propan-1-ol According to a preferred method, the 3TC in a bi-prandial pore is obtained from the 3TC cemented pore by aging the latter in industrial denatured with ethanol / ethanol or in ethanol at an elevated temperature (e.g., 30-70 ° C, particularly about 50 ° C) over a suitable period of time (e.g., 0.5 to 3 hours). particularly about 1 hour or less, long /. . Alternatively, the 3TC in a two-pyropidic solution may at least be achieved by heating the compound in a needle at a toner at a melting point of from 4 to 7 ° C and more preferably above 170 ° C, e.g. above 177-178 ° C, the chick moves to cool down. Another potential for the preparation of 3TC in a biphilmic poem is by crushing or grinding of the compound of the invention. of needle-like crystals. Preferred are the iodine portions of the two-pyramidate crystals and essentially essentially of needle-like crystals. When these crystals (d) are obtained by crystallization or aging in a liquid medium, the compound is obtained, in turn, completely free from needle-like crystals. diC in crystalline form may be used as an antiviral agent as described in -A-D91 / 17159. die in crystalline poros at least to be used as a preparation, and a drug fever useful as an antiviral preparation as described in WG91 / 17159. chi i shows-. dTC in the needle-crystal wall (Terma 1). - o - "*» · # »·« -? * * * * * * * * * * * * * * * * * * * * &Lt; tb &gt; ______________________________________ < tb > ______________________________________ &lt; tb &gt; ha the infrared spectrum of the Crystal I crystals. Figure 4 shows the infrared spectrum of Form II crystals. Figure 5 is a thermogravimetry obtained by differential scanning calorimetry (3SC), crystals; with Figure 1. Figure 6 is a thermogram obtained in di-reeential scanning kelsitersteria of crystals with blister D. The following examples illustrate the invention without limiting it. All weights are given in ° C. benzoate of 5-methoxy-1,3-oxathiola-2-ylethanol A solution of zinc chloride (1.6 g) in hot ethane; A solution of meccaptoacetaldehyde, diethylethyl acetal (34.2 g) and benzoyloxypentaldehyde, LZZ4 (48.3 g) in dilute water (1300 ml) was added with stirring, which was then heated to the reflux temperature of the refluxing glacier under nitrogen for 15 minutes, concentrate, dilute to dryness, and concentrate in vacuo to dryness. (4H), 3.42W, 5.63 (1H), oid (2kg, MegK 9385), eluting with chlorine, wherein (6H), 4.4-4.6 (4H) (1H), 5.46 (1H), 5.47-4.6 (4H), 7.58 (2H), 8.07 (4H); (1RS) -1- (2-benzoyloxymethyl-1,3-oxathiolan-5-yl) - (1 -pyrrolidinyl) (0.92 g), hexamethyldisilazane (50 g) and ammonium sulfate (30 mg) was heated under reflux under nitrogen to give a clear solution. This mixture was cooled and evaporated to a colorless oil which was dissolved in a mixture of nitrogen and acetonitrile (100 g). The solution was added to a cooled ice-cooled solution of benzoate of 5-methoxy-1,3-oxathiolane-2-methanol / meta-linene compound 1 (19.43 g) in acetonitrile (600 g), followed by trimethylsilyllylsulphonate sulfonate 14./ g. The ice bath was removed and the solution was heated under reflux for 45 minutes, cooled and evaporated. The residue was purified by kneading with 1 kg of silica gel (MeOH, 9385) eluting with chloroform / methanol 9ji. the respective fractions were cooled to give a crude residue which was subjected to fractional crystallization from a minimum amount of methanol (approximately 1200 ml) and the resulting compound (6.32 g) was collected in a crystal of white crystals. (1H, s), 7.50-8.00 (6H, m), 6.20 (1H, m), 5.46 (2H, 1H, m / z 3.25 (1H, m). i'nCjjii-Ha-10iJ. 4-amino-1- (2-benzyloxymethyl-1,3-oxathiolan-3yl) - (1H) -pyridin-2-one Method (a) A slurry of cytosine (20.705 g) and ammonium sulfate (several mg) in hexamethyldisilazane (1.0 g) was stirred and heated under reflux for 2. hours under nitrogen. The solvent was removed and the solid residue was separated. Acetonitrile (350 ml). This solution was treated with an elastic needle in an ice cold solution of 5-methoxy-1,3-oxathiolane-2-methanol benzoate (Intermediate 1) (43.57 g) in acetonitrile (650 ml) under stirring and under nitrogen. Trimethylsilyltrisodium methanesulfonate (33 ml) was added, the solution was allowed to warm to room temperature (1.5 h), heated to reflux overnight stay. The resulting mixture was concentrated, diluted with saturated aqueous sodium bicarbonate (500 mL), then extracted with ethyl acetate (3x500 mL). The combined extracts were washed with water (2 x 250 mL) and brine (250 mL), dried over magnesium sulphate and evaporated to give a foam which was subjected to column chromatography on SiO2 g., Ecksk 7734), eluting with a mixture of ethyl acetate / methanol to give a mixture of anomers (approximately 1: 131.59 g). This mixture was crystallized from water (45 mL) and ethanol (9 mL) to give a solid (10.23 g) which was recrystallized from ethanol (120 mL) and water (30 mL) to give the above product white solid (9.26 g); / MeOH / 229.4 mm / E1 / 0 610 /; 272.4 mm / El1 cm 1 cm 293 /; NMR (DMSO-d 6) δ% (s, 3.14 (1H), 3.50 (1H), 4.70 (2H) 7.72 (2H), 8.10 (2H), METHOD (b) To an ice-cold suspension of 1,2,4-triazole (11.65 g) in acetonitrile (120 ml) ) followed by the addition of a solution of (+) - piper-1- (benzoyloxymethyl) -1,3-oxathiolane (10 ml) at room temperature under 15 ° C, Yl) - (1H) -pyrrolidine-2,4-di-9-ene and Intermediate 2 (6.27 g) · · · ·............... · · · · · · · · · · · · · · · · Раз Раз The mixture was cooled with an ice bath and triethylamine (30 ml) and water (21 ml) was added slowly slowly, and the resulting solution was evaporated, the residue was partitioned between saturated sodium bicarbonate solution (400 ml) and chloroform (3 x 200 ml), and the combined organic extracts were dried over magnesium sulfate, filtered and evaporated to give crude product (9.7 g). This product was dissolved in 1,4 -dioxane (240 ml) and a concentrated aqueous solution of alcnane (a specific gravity of 0.880, 50 ml) was added. After 1.5 hours, the solvent was evaporated and the residue was dissolved in ethanol. This causes sedimentation of a solid which is filtered off. the mother liquors were purified by silica gel column chromatography (Kieselgel 9385, 600 g). The resulting fractions were combined and evaporated to give the title compound as an oil (2.18 g), identical to that obtained in the form of the title compound (a), in the form of a white solid (2.18 g). 4-Amino-1- (2-hydroxymethyl) -1,3-oxathiol ac-5-aza-1H-pyridin-2-one A suspension of cis -4 (1 H) -pyrrolidin-2-one (Intermediate 3) (8.19 g) and Amberlite IRA-400 (OH), resin (8.24 g) in methanol (250 ml) was stirred and heated to reflux for 1 h. The titanium dioxide was removed by rustling and then folded with methanol. The resulting diethyl ethers are evaporated and the residue is treated with ethyl acetate (80 ml). The resulting white solid was collected by filtration to give the crude product (510 g) .1H NMR (DMSO-d6) δ 3.04 (111), 3.40 (1H), 3.73 (2H), 5.18 (III), 5.59 (111), 5.73 (111), 6.21 (111), 7.13 (211), 7.81 (111). (2-hydroxymethyl-1,3-oxathiol-5-yl) - (1H) -pyrimidin-1-yl] 2-one 1 / Three 50-ml aliquots of a nutrient broth /

Lct. lt; / RTI &gt; cells were incubated overnight at 37 ° C with shaking at 250 rpm and then each flask was used 3 g / l Magnesium stearate, 0.2 g / l Potassium sulfate 2.5 g / l Sodium chloride 2.3 g / l Na2 PO4 0.2 g / l NalpPO 2 .2H 2 O, 0.6 g / L, cctcdine, 1.2 g / L) in a sedimentary aureus, cultures fermented at 750 rpm, 37 ° C and auricarp 4 ml / min. After culturing for 24 hours, the cells collected by centrifugation (5000 g, 30 rpm), k The 72 g of wet heat was then poured into 200 ml of 20 ml of TBS Buffer (pH 7.5) and sonicated (4x5 sec) at room temperature. by centrifugation (58,000 ml, 80 min) and precipitated to 76% saturation in the supernatant, precipitated with Opra by centrifugation (30,000 g, 30 min) and the cell lasagne resuspended in 25 ml U.S.A. (100 mg, pH 7.0), ammonium nitrate (70% paste). The solution was prepared by centrifugation at 12,000 rpm 30 mM. The supernatant was removed and the solid mass was dissolved in Tris HCl buffer (pH 7.0); 100 da / to the initial eight. 11 _______ ______ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __

. (1 ml) was added dropwise (100 ml) and stirred. Enzyme solution (0.5 ml) was added and the mixture was maintained at constant pH by the continuous addition of HCl (25 mm). The conversion was monitored by high pressure liquid chromatogradil which showed that the (+) enantiomer of the substrate was mostly deamidated. After 22 hr (+) the enantiomer of the substrate (KT 12.5 min) was completely removed and the pH of the solution was adjusted to 10.5 by addition of the coc. sodium hydroxide. The solution obtained above is eluted through a column of OT-QAE 'Sepixx / A25; fftarmacta; 30x1.6 cm), pre-equilibrated to pH 11. The column was washed with water (200 ml) and then with HCl (0.1 M). The fractions (40 mL) were analyzed by high pressure liquid chromatography with reverse phase-a-1a containing the sub-cutaneous enantiomer of the substrate and the mixture was diluted with of-trieAspora. Analysis of chiral liquid chromatography on peaks at ambient pressure indicates that the title compound is a mixture consisting of opidine enantio-er (KT 10.2 min) as the major component and the other analyzer (ET 8.5 min) as a minor component (90%). 3 / step (2) is repeated in larger quantities. The compound obtained in Example 1 (363 g ±) in 250 ml of water was seeded with an enzyme solution (O.) prepared as shown in Table 1. further, aliquots of the enzyme (0.5 ml) were added after 18 and 47 hours. The reaction mixture was stirred for 70 hours, then allowed to stand for 64 hours. High pressure chiral chromatographic chromatographic analysis indicates that the (+) enantiomer of the sucistate is completely deaminaminated. The pH of the resulting precipitate was adjusted to 100 for base. HL H-mn ', 000.0.0.-00 O. SOD * LH.pxp. CIDDL; IRIS, KO; ¿½, ¿½ ½ ½ ½ ½ ½, ICOGCfG xoen / 1 /. Molecular Cloning, Molecular Cloning, Molecular Cloning, 00? And u-3. * * * * * * * * * * * * * ¿½ ¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿ to 7.5 ° C, to 25 ° C, to give the title compound as a yellow solid and to neutralize the title compound as a white solid by the same solvent. (II) and (II) and (II) and (II) and (II) of this second chlorine contain no organic compounds. erection 70 contains the deaerated blower. (2) and (3) are staggered to be inwardly engaged. , to pli 7.5. The solution was eluted with an orange solution from oAD-16 / z1 x 2.4 g / l in water and water. The blade was applied with water in a mixture of 2: 1 acetone / water (1: 4 v / v). / RTI &gt; The desired (-) enantiomer was obtained as a white powder (190 mg) as a white powder (190 mg) and the title compound Methods for liquid chronotrophic high pressure are given in the following characteristics: 1. Analytical tensile strength of a high pressure C and 9 N &apos; pp3.xxx ieUJIOHcl * Main filling Spilerps orb ODS -2/5 mD / d ... 0 x ο. A solution of the title compound as described in Example 1, wherein R is as defined in Claim 1, *: 1: 4.0c, (dec): UV, 270nm Bp &lt; + &gt;, BO3 .pp 1; 1p.-OJIIO 1.05-132 5.5 min 13 2 Chiral Analytical Time of High Pressure Column: Cyclobutan I Acetyl 250 x 4.6 g Eluent: 0.2% Triethylammonium Acetate (pH 7.2) / Velocity 1.0 ml / min Proof: Recovery milking: by UV reading, 270 nm BON 189 11.0 and 12.5 min deaminated BCH-189 8.5 and 10.2 min / Stopping the peak peak at ± 2.min and mice .10.2 min.) Example 1 Susp (50 mg) was heated to 45 ° C to give a solution of the title compound (5) (64.8 g) in water (200 mg) to give a solution. The product is crystallized upon non-agitation of the frame, the aliphatic is discontinued and the suspension is stirred at 10 ° C for 10 hours. The suspension is stirred at 10 ° C for 1 hour. P-p-phenoxy) -piperidine; 2 x 30 and dried in vacuo at 454 samples to obtain 3TC as a solution i / fine needle crystal. The procedure has an infrared spectrum and a thermogravimetric scanning calorifier identical to o-niw O -t 1 0 Example 2 Compound of formula (I) as an admixture of a compound of formula (I): ???????????? · · · · · · · · * * * *. in-air, airborne alcohols ZibS: 50 g; heated to reflux temperature to give a bis-solution. The solution was combusted and the cisplatin was distilled at atmospheric pressure until 100 l of 10% of the solution remained. Stem crystals of authentic material are added to the solution and allowed to cool from 80 to 25 ° C for 1 hour. Crystallization begins at 7 ° C. The slurry is stirred at 15 ° C for 1 hour. The product was isolated by filtration and was digested with IMS (10 μl); 1 peel). After vacuum-suction, the title compound was obtained as agglomerates of dipotamers (8.42 g), m.p. 179-181 ° C. 4-amino-1- (2-hydroxyethyl) -1,1-oxathiol-5-yl] -N-pyrrolidin-2-one. phenoxyphenol: C, 4, 9; Calcd: C, 41.9; H, 4.8; X, 18.38. The compound has an infrared spectrum and a terragraph differential slope, e.g., shielded and altered. Example 3 A suspension of the product, 1: 1, 20: 2, in a mixture of ethyl alcohol / m / z; 0.01 l; in volume / volume was separated by the addition of a small amount (approximately 80%) to a temperature of about 50 ° C, and the result was a microscope and a scanning calorimetry / RTI &gt; The sample is 100% form II / disopyralidal habitus /. hours, and the Uhmosphere is inaugurated in one of the most famous sessions. The solution was stirred at room temperature for 2 hours and the solution was stirred at room temperature for 2 hours. The suspension was filtered and the filtrate was refluxed for 2 hours. / ml ml; (1: 8), and dried in vacuo to give an off-white crystalline solid (17.13 g), namely (-) - trans -4-hydroxy-1- (2hydroxymethyl-1,3- yl) - (1H) -pyrimidin-s-one, m.p. 180-181 ° C. Analytically found: b, 41.8 g, H, 4.dbd

Calculated for C18 H18 Cl2 Cl2 Cl2 Cl2 Cl2 Cl2 Cl2 Cl2 Cl2 Cl2 Cl2 BrCl2: C, H, 4 and 6, respectively. Example 4 Primary X-ray Assay Data for the Colostrum:

C 1 -C 10 -cyclohexylcarbamoyl-1-oxazolidinone, 1,1-dioxide, , v - <l / h / s. / 4i yes. LCMS (CDCl3), reflected (2 = 0.5). 4H2-1H (4-HO), Z.-O. Are OX w a. 960, weight / Ctb-Ka / = 27.5 cm-1. Understand the crystal 0.48 x 0.32 x 0.30 microns of crystalline crystals of light diffractograms were assayed by gelatin beads. Altogether, the IbCl deflected / 3 <21 <115 / on a Siemens D-spectrometer is deduced. with a chromaticity. - Radiation, using the 3 / W scans, the structure is resolved by direct motions of non-discrete atmospheres. Hydrogenated carbon atoms are idealized (C = O, 0.96A) to provide carbon-carbon starting materials. the hydrogen atoms, at -OH and -OH groups, with an alpha-my papillogene of difference 16 or a Foure map. All hydrogen atoms are absent. The fugitive coefficient is the value of K = 0.068, K is 0.069, w = IS / F / + 0.005 IFI, the maximum residual electron density is 0.45 eA. Absolute chirality is confirmed using the Rodnars test Ih = 0.99 / 9/1. Example 5 Pharmaceutical Compositions (a) 100 mg Tablets Ingredients for one tablet 3TC 100.0 mg microcrystalline cellulose NF 189.5 mg Sodium starch glycolate NF 9.0 mg Lactose stearate NF 1.5 mg Total weight 300.0 mg The compound 3C (II), the microcrystalline cellulose and the sodium starch glycollate are sieved and mixed in a nozzle for 15 minutes. The sieved magnesium salt is added to this mixture and the blending is continued for a further 2 minutes. The mixture is pressed into a standard tabletting machine and then covered with a dilute Aqueous Opactry suspension to give an aesthetic appearance Tablets (b) 300 mg Tablets Tablets are formulated as described in U.S. Pat. Nos. 5,365,804 and 5,050, respectively. Tablets are formulated as described in U.S. Pat. above for / a /.

Claims (3)

-17-yl-thymidine. (2-hydroxy-1,3-oxathiazan-1-yl) - (1H) -pyridin- 1-hydroxy-2-one in crystalline form. 2. cis-4-Amino-1- (2-hydroxymethyl-1, p-oxathiolan-oyl) - (1 H) -pyridin-2-one in the a? 3. A crystalline standard as claimed in claim 1 or 2, characterized in that the crystalline form of the crystalline form of the compound of formula A crystalline rule according to any one of claims 1 to 3, characterized in that the point is not 177-173 ° C. 5. Crystalline form according to claim 1, 1 to 4, characterized in that the ratio of the spacing between the 920 and 850 wavelengths is as follows: Crystalline euron according to claims 1 to 5, TTTQ P01-P10-XxX-4-cd with Px-O-inar 1C cd a / A-1'ijl vUCd-dP ii Qii-xx-Px77 received Hcpi'ia, ATpkSpO posteNNI-T from T .mu.Ci o, x ~ 1 a. • '-sd / hhChsa. - -' DR is οα. 0 loop vcltiS. K3C1C1C4C1 aXi-pro X with c t with the problem? 4-yl) -1H-imidazol-1-yl] -2-propylamino] -1H-imidazol- In the embodiment of the present invention there is disclosed a method for the preparation of a medicament for the treatment of chronic hepatitis C viruses, ¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿ Pir mEB-1 ". -18- ..... ····,.: '11. Crystalline laryngeal, or 3 to 10, characterized by the fact that the ester is at a temperature of 124-127 ° C in its differential scanning calorimetry profile. A crystalline crystal according to any one of claims 1 to 8, characterized in that it has an absorption spectrum in its infrared spectrum at about 1110 wavelengths. 13. (-) - cis -4-allyl-1- (2-hydroxyethyl) 1,3-oxathiazan-5-yl) pyridin-2-one in a crystal column, 14. cis-4-amino-1- [2- (hydroxy) ethyl] -1,3-oxathiolylidene] -cyclopropyl] quot ;, as in FIG. (-) - cis-m-alpha-t-butyldimethylsilyl-p-oxazolidin-1-yl) and the infrared spectrum as shown in Figure 3. 16. (-) - cis -4-hydroxy-1- (2-hydroxypentyl) -1,3-oxathiolane -Pyrimidin-2-one in a crystalline dome and an inert solvent such as 1N sodium hydroxide. Preparation of (-) - cis-4-ammo-1- (2-methyl- 1,3- oxazolan- 5- yl) - 1 H- 1 -imidazol- 2 -one in crystallisation, lt; RTI ID = 0.0 &gt; aqueous solution. &lt; / RTI &gt; 18. A process for the preparation of (-) - cis-n-amino-1- (2-hydroxyethyl-1,3-oxathiolan-oyl) - (1H) -pyridin-2-one crystalline herol, that the aqueous solution of the aqueous solution of the compound with a span- 1-ol. / 2 lfrOK ЧУ. ethyl-1-cyclopentyl-4-methyl-1H-indole-2-carboxylic acid- , $ ¿¿¿¿¿¿¿¡¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿ ур д ba ba ba 29 29 29 29 29...... 19. The process according to claim 19, wherein the non-aqueous medium is selected from ethanol or sodium carbonate. 15. A process as claimed in claim 19, wherein the non-aqueous medium is selected from ethanol, ¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿ -ZZ · 2e. to produce (-) - cis-4-α-quino-1- (2-hydroxy-1,3-oxadiazol-4- yl) pyrrolo [ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ t ^ ; Λ &amp; m-BuOt 0x-1i; "Xx x x x x x x x x x x x xx xx x x x x x x x x x x x x x x x x x x x x x x x x x x x xx xx x x x xx xx xx xx xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx ¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿ (1,3-dioxan-1,3-benzodiazepin-3-yl) -cyclohexanecarboxylic acid. ¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿¿ Я 2D. i_y eou. heard> J eu-Xx ->> J ÜXhhhhhhhhh heard L X. X-xxx-xxxx-xxxx xxxx xxxx xxxx xxxx xxxx xxxx xxxx xxxx xxxx xxxx xxxx xxxx xxxx xxxx xxxx xxxx xxxxxx xxxxxx xxxxxx xxxxxx xxxxxx xxxxxx xxxxxx xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 1989. Abstracts T.C. 01. and.-., 0.9.63 9-P-A9P9 V99 9 Al. N / A / N / A / N / A 3. PCT / SE91 / 0C706 / W091 / 17159 /